Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors. It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to tumor metastasis. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology. Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis. Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren""s syndrome, myopia, ocular tumors, ocular angiogenesis/neo-vascularization and corneal graft rejection. For recent reviews, see: (1) Recent Advances in Matrix Metalloproteinase Inhibitor Research, R. P. Beckett, A. H. Davidson, A. H. Drummond, P. Huxley and M. Whittaker, Research Focus, Vol. 1, 16-26, (1996), (2) Curr. Opin. Ther. Patents (1994) 4(1): 7-16, (3) Curr. Medicinal Chem. (1995) 2: 743-762, (4) Exp. Opin. Ther. Patents (1995) 5(2): 1087-110, (5) Exp. Opin. Ther. Patents (1995) 5(12): 1287-1196.
TNF-xcex1 converting enzyme (TACE) catalyzes the formation of TNF-xcex1 from membrane bound TNF-xcex1 precursor protein. TNF-xcex1 is a pro-inflammatory cytokine that is now thought to have a role in rheumatoid arthritis, septic shock, graft rejection, cachexia, anorexia, inflammation, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance and HIV infection in addition to its well. documented antitumor properties. For example, research with anti- TNF-xcex1 antibodies and transgenic animals has demonstrated that blocking the formation of TNF-xcex1 inhibits the progression of arthritis. This observation has recently been extended to humans as well.
It is expected that small molecule inhibitors of MMPs and TACE therefore have the potential for treating a variety of disease states. While a variety of MMP and TACE inhibitors have been identified and disclosed in the literature, the vast majority of these molecules are peptidic and peptide-like compounds that one would expect to have bioavailability and pharmacokinetic problems common to such compounds that would limit their clinical effectiveness. Low molecular weight, potent, long acting, orally bioavailable inhibitors of MMPs and/or TACE are therefore highly desirable for the potential chronic treatment of the above mentioned disease states.
Recently, two references have appeared (U.S. Pat. No. 5,455,258 and European Patent Appl. 606,046) that disclose arylsulfonamido-substituted hydroxyamic acids. These documents cover compounds exemplified by CGS 27023A. These are the only non-peptide matrix metalloproteinase inhibitors disclosed to date. 
Salah et al., Liebigs Ann. Chem. 195, (1973) discloses some aryl substituted thio and aryl substituted sulfonyl acetohydroxamic acid derivatives of general formula 1. These compounds were prepared to study the Mannich reaction. Subsequently, they were tested for their fungicidal activity. 
Some sulfone carboxylic acids are disclosed in U.S. Pat. No. 4,933,367. Those compounds were shown to exhibit hypoglycemic activity.
The present invention relates to novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-xcex1 converting enzyme (TACE) for the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HTV infection.
In accordance with this invention there is provided a group of compounds of general formula I 
wherein:
R1 is alkyl of I to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R5;
cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R5;
saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, optionally substituted with one or two groups selected independently from R5;
or heteroaryl-(CH2)0-6xe2x80x94 wherein the heitroayl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R5;
A is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or SO2xe2x80x94;
R2 and R3, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring contaning O, S or Nxe2x80x94R7 optionally having one or two double bonds;
R4 is hydrogen,
alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R5;
alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
phenyl or naphthyl optionally substituted with one or two groups selected independently from R5;
C3 to C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R5;
saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, optionally substituted with one or two groups selected independently from R5;
R5 is H, C7-C11 aroyl, C2-C6 alkanoyl, C1 to C12 alkyl, C2 to C12 alkenyl, C2-C12 alkynyl, F, Cl, Br, I, CN, CHO, C1-C6 alkoxy, aryloxy, heteroaryloxy, C3-C6 alkenyloxy, C3-C6 allyloxy, C1-C6 alkoxyaryl, C1-C6 alkoxyheteroaryl, C1-C6 alkylamino-C1-C6 alkoxy, C1-C2 alkylene dioxy, aryloxy-C1-C6 alkyl amine, C1-C12 perfluoro alkyl, S(O)nxe2x80x94C1-C6 alkyl, S(O)n-aryl where n is 0, 1 or 2; OCOO C1-C6 ayl, OCOOaryl, OCONR6, COOH, COO C1-C6 alkyl, COOaryl, CONR6R6, CONHOH, NR6R6, SO2NR6R6, NR6SO2aryl, xe2x80x94NR6CONR6R6, NHSO2CF3, SO2NHheteroaryl,SO2NHCOaryl, CONHSO2-C1-C6 alkyl, CONHSO2aryl, SO2NHCOaryl, CONHSO2-C1-C6 alkyl, CONHSO2aryl, NH2, OH, aryl, heteroaryl, C3 to C8 cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, wherein C1-C6 
alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alyl, C1-C6 alkoxy, or hydroxy;
R6 is H, C1 to C8 alkyl optionally substituted with OH; C3 to C6 alkenyl, C3 to C6 alkyl, C1 to C6 perfluoro alkyl, S(O)n-C1-C6 alkyl S(O)n aryl where n is 0, 1 or 2;, or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
and R7 is C7-C11 aroyl, C2-C6 alkanoyl, C1-C12 perfluoro alkyl, S(O)nxe2x80x94C1-C6-alkyl, S(O)n-aryl where n is 0, 1 or 2; COO-C1-C6-alkyl, COOaryl, CONR6, CONR6R6, CONHOH, SO2NR6R6, SO2CF3, SO2NHheteroaryl, SO2NHCOaryl, CONHSO-C1-C6-alkyl, CONHSO2aryl, aryl, or heteroaryl, where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C1-C6 alkyI, C1-C6 alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or Nxe2x80x94C1-C6 alkyl;
alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
alkynyl 3 to 8 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R5;
heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R5;
biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R5;
arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R5;
cycloalkylalyl or bicycloalylakyl of 4 to 12 carbon atoms, wherein the cycloalkyI or bicycloalkyl group is optionally substituted with one or two groups selected independently from R5;
saturated or unsaturated mono or bicyclic heterocycle containilg one heteroatom selected from O, S or Nxe2x80x94C1-C6 alky, optionally substituted with one or two groups selected independently from R5; or
R8R9N-C1-C6-alkoxyaryl-C1-C6-alkyl where R8 and R9 are independently selected from C1-C6 alkl or R8 and R9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;
and the pharmaceutically acceptable salts thereof.
A more preferred aspect of the present invention is the group of compounds of general formula (Ia): 
wherein:
R1 is alkl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
aryl of 6 to 10 carbon atoms, optionally substituted with one to two groups selected independently from R5;
cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one to two groups selected independently from R5;
saturated or unsaturated mono or bicyclic heterocycle of from 5 to 10 members containing one heteroatom selected from O, S or NR7, optionally substituted with one to two groups selected independently from R5;
or heteroaryl-(CH2)0-6- wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R5;
A is xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or SO2xe2x80x94;
R2 and R3, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or Nxe2x80x94R7 optionally having one or two double bonds;
R4 is hydrogen,
alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R5;
alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently fronm R5;
alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
phenyl or naphthyl optionally substituted with one or two groups selected independently from R5;
C3 to C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R5;
R5 is H, F, Cl, Br, I, CN, CHO, C7-C11 aroyl, C2-C6 alkanoyl, C1 to C12 alkyl, C2 to C12 alkenyl, C2-C12 alkynyl, C1-C6 alkoxy, aryloxy, heteroaryloxy, C3-C6 alkenyloxy, C3-C6 alknyloxy, C1-C6 alkoxyaryl, C1-C6 alkoxyheteroaryl, C1-C6-alkylamino-C1-C6 alkoxy, C1-C2-alkylene dioxy, aryloxy-C1-C6 alkyl amine, C1-C12perfluoro alkyl, S(O)n-C1-C6 alkyl, S(O)n-aryl where n is 0, 1 or 2; OCOO-C1-C6 alkyl, OCOaryl, OCONR6, COOH, COO-C1-C6 alyl, COOaryl, CONR6R6, CONHOH, NR6R6, SO2NR6R6, NR6SO2aryl, NR6CONR6R6, NHSO2CF3, SO2NHheteroaryl, SO2NHCOaryl, CONHSO2-C1-C6 alkyl, CONHSO2aryl, SO2NHCOaryl, CONHSO2-C1-C6 alkyl, CONHSO2aryl, NH2, OH, aryl, heteroaryl, C3 to C8 cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7;
wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
R6 is H, C1 to C18 alkyl optionally substituted with OH; C3 to C6 alkenyl, C3 to C6 alkynyl, C1 to C6 perfluoro alkyl, S(O)n alkyl or aryl where n is 0, 1, or 2; or COheteroaryl;
wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from 0, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
and R7 is C7-C11 aroyl, C2-C6 alkanoyl, C1-C12 perfluoro alkyl, S(O)n-alkyl, S(O)n-aryl where n is 0, 1 or 2; COalkyl, COOaryl, CONHR6, CONR6R6, CONHOH, SO2NR6R6,SO2CF3, SO2NHheteroaryl, SO2NHCOaryl, CONHSO2alkyl, CONHSO2aryl, aryl, heteroaryl; wherein C1-C6 alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
arylalkyl of 7 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R5;
heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R5;
biphenylalkyl of 13 to 18 carbon atoms, wherein biphenyl is optionally substituted with one or two groups selected independently from R5;
arylalkenyl of 8 to 16 carbon atoms, wherein aryl is optionally substituted with one or two groups selected independently from R5;
cycloalkylalkyl or bicycloalrlalkyl of 4 to 12 carbon atoms, wherein cycloalkyl or bicycloalkyl is optionally substituted with one or two groups selected independently from R5;
saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or N-C1-C6 alkyl, optionally substituted with one or two groups selected independently from R5;
R8R9N-C1-C6-alkoxyaryl-C1-C6-alkyl where R8 and R9 are independently selected from C1-C6 alkyl or R8 and R9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;
and the pharmaceutically acceptable salts thereof.
The most preferred group of compounds are those of the following formula (Ib): 
in which
R1 is phenyl, naphthyl, alkyl of 1-18 carbon atoms or heteroaryl such as pyridyl, dienyl, imidazolyl or furanyl, optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryloxy, heteroaryloxy, C3-C6 alkenyloxy, C3-C6 alkyloxy, halogen; or S(O)n-C1-C6alkyl C1-C6 alkoxyaryl or C1-C6 alkoxyheteroaryl;
A is xe2x80x94Sxe2x80x94, xe2x80x94SO or xe2x80x94SO2xe2x80x94;
R2 and R3, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or Nxe2x80x94R7 optionally having one or two double bonds;
R4 is hydrogen,
alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R5;
alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
phenyl or naphthyl optionally substituted with one or two groups selected independently from R5;
C3 to C8 cycloalkyl or bicycloallyl optionally substituted with one or two groups selected independently from R5;
R5 is H, C7-C11 aroyl, C2-C6 alkanoyl, C1 to C12 alkyl, C2 to C12 alkenyl, C2-C12 allynyl, F, Cl, Br, I, CN, CHO, C1-C6 alkoxy, aryloxy, heteroaryloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, C1-C2 alkylene dioxy, aryloxy-C1-C6 alkyl amine, C1-C12 perfluoro alkyl, S(O)n-C1-C6 alkyI, S(O)n-aryl where n is 0, 1 or 2; OCOO C1-C6 aLkyl, OCOOayl, OCONR6, COOH, COO C1-C6 alkyl, COaryl, CONR6R6, CONHOH, NR6R6, SO2N 6R6, NR6SO2aryl xe2x80x94NR6CONR6R6, NHSO2CF3, SO2NHheteroaryl,SO2NHCOaryl, CONHSO2-C1-C6 alkyl, CONHSO2aryl, SO2NHCOaryl, CONHSO2-C1-C6 alkyI, CONHSO2aryl, NH2, OH, aryl, heteroaryl, C3 to C8 cycloalkyl; saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, wherein C1-C6 aLkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
R6 is H, C1 to C18 alkyl optionally substituted with OH; C3 to C6 alkenyl, C3 to C6 alkynyl, C1 to C6 perfluoro alkyl, S(O)n alkyl or aryl where n is 0, 1 or 2; or COheteroaryl; wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR7 and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
and R7 is C7-C11 aroyl, C2-C6 alkanoyl, C1-C12 perfluoro alkyl, S(O)n-alkyl, S(O)n-aryl where n is 0, 1 or 2; COOalkl, COOaryl CONHR6, CONR6R6, CONHOH, SO2NR6R6,SO2CF3, SO2NHheteroaryl, SO2NHCOaryl, CONHSO2alkyI, CONHSO2aryl aryl, or heteroaryl; where aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected independently from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy; and heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or Nxe2x80x94C1-C6 alkyl;
alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
arylalkyl of 7 to 16 carbon atoms, optionally substituted with one or two groups selected independently from R5;
heteroarylalkyl wherein alkyl is from 1 to 6 carbon atoms and heteroaryl contains 1 or 2 heteroatoms selected from O, S or N and is optionally substituted with one or two groups selected independently from R5;
biphenylalkyl of 13 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
arylalkenyl of 8 to 16 carbon atoms, optionally substituted with one or two groups selected independently from R5;
cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, optionally substituted with one or two groups selected independently from R5;
saturated or unsaturated mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR-C1-C6 alkyl, optionally substituted with one or two groups selected independently from R5;
R8R9N-C1-C6-alkoxyaryl-C1-C6-alkyl where R8 and R9 are independently selected from C1-C6 alkyl or R8 and R9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;
and the pharmaceutically acceptable salts thereof.
The most preferred matrix metalloproteinase and TACE inhibiting compounds of this invention are:
1-benzyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,
4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide,
1-(3,4-dichlorobenzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxamide,
4-(4methoxy-benzenesulfonyl)-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxamide,
4-(4-methoxy-benzene-sulfonyl)-1-napthalene-2-yl-methylpiperidine-4-carboxylic acid hydroxamide,
1-biphenyl-4-ylmethyl-4-(4-methoxy-benzenesulfonyl)piperidine-4-carboxylic acid hydroxamnide,
4-(4-methoxy-benzene-sulfonyl)-1-(3-methyl-but-2-enyl)piperidine-4-carboxylic acid hydroxamide,
1-(4-bromo-benzyl)4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,
4-(4-methoxy-benzenesulfonyl)-1-(3-phenyl-propyl)-piperidine-4-carboxylic acid hydroxyamide,
1-tert-butyl-4-(4methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,
1-butyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,
1-cyclooctyl-4-(4methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,
1-ethyl-4-(4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,
1-isopropyl-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyarnide,
1-methyl-4-(4-methoxy-benzenesulfonyl)-piperidine4-carboxylic acid hydroxyamide,
1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,
1-(4-fluoro-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,
1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,
4-(4-methoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide,
4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)ethyl]-piperidine-4-carboxylic acid hydroxyamide,
4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid hydroxyamide,
4-(4-n-butoxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide,
4-(4-methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide,
4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide,
4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid hydroxyamide,
4-(4-n-butoxy-benzenesulfonyl)-1-(2phenoxyethyl)-piperidine-4-carboxylic acid hydroxyamide,
4-(4-methoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide,
1-Benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,
4-(4-Butoxy-benzenesulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide,
4-(4-Butoxy-benzenesulfonyl)-1-[3-(2-morpholinyl-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid hydroxyamide,
1-Methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,
1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,
1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,
4-[4-(4-chloro-phenoxy)-benzenesulfonyl]1-methyl-piperidine-4-carboxylic acid hydroxyamide,
4-[4-(4-chlorophenoxy)-benzenesulfonyl]1-ethyl-piperidine-4-carboxylic acid hydroxyamide,
1-Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide,
1-Benzyl-4-[4-(4-chorophenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide,
1-Benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide,
1-Butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide,
1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxyamide,
4-(4-butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid hydroxyamide,
4-(4-Methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperdine-4-carboxylic acid hydroxyamide,
4-(4-methoxy-benzenesulfonyl)-1-(4-pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide,
1-(3,4-Dichlorobenzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide,
[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid hydroxamide,
4-(4-Butoxy-benzenesulfonyl)-1-(3-phenoxy-benzyl)-piperidine-4-carboxylic acid hydroxamide,
[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-(4-methylbenzyl)-piperidine-4-carboxylic acid hydroxamide,
4-(4-Butoxy-benzenesulfonyl)-1-(4methylbenzyl)-piperidine-4-carboxylic acid hydroxamide,
4-(4-Butoxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylic acid hydroxamide, and
4-(4-Butoxy-benzenesulfonyl)-1-pyridin-4-ylmethyl-piperidine-4-carboxylic acid hydroxamide, and pharmaceutical salts thereof.
It is understood that the definition of the compounds of formulas I, Ia and lb, when R1, R2, R3 and R4 contains asymmetric carbons, encompass all possible stereoisomers and mixtures thereof which posses the activity discussed below. In particular, it encompasses racemic modifications and any optical isomers which possesses the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques. Where not stated otherwise, the term xe2x80x9calkylxe2x80x9d refers to a straight or branched C1-C6 alkyl group and aryl is phenyl or naphthyl. The phandmceutically acceptable salts are those derived from pharmaceutically acceptable organic and inorganic acids such as lactic, citric, acetic, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfiric, methanesulfonic, and similarly known acceptable acids.
The present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of compound of this invention and a pharmaceutically acceptable carrier.
The compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example, parenteral administration for patients.
In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules, and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg per kg. Such composition may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
The compositions of the invention may be formulated with conventional excipients, such as fillers, a disintegrating agent, a binder, a lubricant, a flavoring agent, and the like. They are formulated in conventional manner.
Also according to the present invention, there are provided processes for producing the compounds of the present invention.
The compounds of the present invention may be prepared according to one of the general processes out lined below.
The appropriately substituted mercaptan derivative was allated using either substituted (Scheme I) or unsubstituted ( Scheme 2) xcex1-bromo acetic acid ester derivative in refluxin acetone using K2CO3 as base. The sulphide derivative thus obtained was oxidized using m-chloroperbenzoic acid in CH2Cl2 or by using Oxone in methanol/water. The sulfone obtained from the above mentioned process can be either filrter alkylated using variety of alkyl halides to obtain the disubstituted derivative or it can be hydrolyzed using NaOH/MeOH at room temp. However instead of using the ethyl ester, if the tertiary butyl ester is present, the hydrolysis can be carried out with TFA/CH2Cl2 at room temperature. Subsiquently, the carboxylic acid obtained was converted to the hydroxamic acid derivative by reaction with oxalyl chloride/DMX (catalytic) and hydroxyl amine/triethyl amine. 
As outlined in Scheme 3, the sulfide derivative can be flirter allylated using lithium bis(trimethyl silyl)amide in THF at 0xc2x0 C. The alkylated or mono substituted compound was hydrolyzed and converted to the hydroxamic acid derivative. The sulfinyl derivatives were prepared by oxidizing the sulfide hydroxamic acid derivatives with H2O2 in MeOH solution. 
The corresponding 1-substituted-4-(4methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamides were prepared startng from diethanolamine and appropriately substituted alkyl or aryl halides (Scheme 4). The N-substituted diethanol amine derivatives were converted to the dichioro compounds using thionyl chloride. The corresponding dichlorides were reacted with substituted sulfonyl acetic acid ethyl ester derivatives in the presence of K2CO3/18-Crown-6 in boiling acetone. 1-substituted-4-(methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl esters thus obtained were converted to the hydroxy amide as outlined in Scheme 4. Alternatively these classes of compounds and other hetrocycles can be prepared as indicated in Scheme 5 and 6. 
Alternatively, Schemes 7 to 11 show methods for the preparation of hydroxamic acid compounds using a solid phase support (P). 
Reagents and Conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25xc2x0 C.; 2-16 hours. b) Thiol (5.0 eq.); sodium iodide (5.0 eq.); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0 eq.); THF; 25xc2x0 C.; 12-16 hours. c) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid (2.0 eq.); DCM; 25xc2x0 C.; 12-24 hours. d) mCPBA (5.0 eq.); DCM; 25xc2x0 C.; 12-24 hours. e) TFA: DCM (1:1); 25xc2x0 C.; 1 hour.
The 4-O-methylhydroxylamine-phenoxymethylopoly(styrene-1%-divinylbenzene)-resin (hydroxylamine resin) may be coupled with a 2-halo acid to give the hydroxamate ester resin. The coupling reaction may be carried out in the presence of carbodiimide, such as DIC, in an inert solvent such as DMF at room temperature. The halogen group may be displaced with a thiol in the presence of a base, such as DBU, in an inert solvent such as THF at room temperature. The sulfide may be oxidized to the sulfoxide by reaction with an oxifig agent such as tert-butylhydroperoxide in the presence of an acid catalyst such as benzenesulfonic acid, in an inert solvent such as DCM at room temperature. Alternatively, the sulfide may be oxidized to the sulfone by reaction with an oxidizing agent such as meta-chloroperoxybenzoic acid, in an inert solvent such as DCM at room temperature. The sulfide, sulfoxide, or sulfone may be treated with and acid, such as trifluoroacetic acid, in and inert solvent such as DCM to hlberate the fee hydroxamic acid.
Scheme 8 shows a method of preparing hydroxamic acids having alkoxy groups attached to the aromatic ring. 
Reagents and Conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotriazole hydrate (HOBt, 6,0 eq.) 1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25xc2x0 C.; 2-16 hours. b) 4-Fluorobenzenethiol (5.0 eq.;) sodium iodide (5.0 eq.); 1,8-diazabicycle[5.4.0]undec-7-ene (DBU, 3.0 eq.); THF; 25xc2x0 C.; 12-16 hours. c) Alcohol (15.0 eq.); sodium hydride (15.0 eq.); DMF; 80xc2x0 C.; 15 hours. d) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid (2.0 eq.); DCM; 25xc2x0 C.; 12-24 hours. e) mCPBA (5.0 eq.); DCM; 25xc2x0 C.; 12-24 hours. f) TFA: DCM (1:1); 25xc2x0 C.; 1 hour.
The hydroxylainie resin may be coupled with the 2-halo acid and the halo group may be displaced by fluorobenzenethiol as previously described. The fluoro group may then be displaced with an alcohol in the presence of a base such as sodium hydride, in an inert solvent such as DMF at about 80xc2x0 C. The alkoxybenzenesulfanyl hydroxamate ester may then be oxidized either to the corresponding sulfinyl or sulfonyl hydroxamate ester as previously described. The free hydroxamic acids may be liberated as previously descnied
Scheme 9 shows a method of preparing 2-bisarylsulfanyl-, sulfinyl-, and sulfonylhydroxamic acids. 
Reagents and conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.); 1,3-diisopropylcarbodiiliimde (DIC, 4.0 eq.); DMF, 25xc2x0 C.; 2-16 hours. b) 4-Bromobenzenethiol (5.0 eq.); sodium iodide (5.0 eq.); 1,8diazabicyclo[5.4.0]undec-7ene (DBU, 3.0 eq.); THF; 25xc2x0 C.; 12-16 hours. c) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid (2.0 eq.); DCM; 25xc2x0 C.; 12-24 hours. d) mCPBA (5.0 eq.); DCM; 25xc2x0 C.; 12-24 hours. e) Arylboronic acid (2.0 eq.); tetrakis(triphenylphospliine) palladium(0) (0.1 eq.); 10% aqueous sodium carbonate (10.0 eq.); DME; 80xc2x0 C.; 8 hours. f) TFA: DCM (1:1); 25xc2x0 C.; 1 hour.
The hydroxylamine resin may be coupled with the 2-halo acid and the halo group may be displaced by bromobenzenethiol as previously described. The bromobenzenesulfanyl hydroxamate ester may then be oxidized either to the corresponding sulfinyl or sulfonyl hydroxamate ester as previously described. The bromo group may then be replaced with an aryl group by reaction with the arylboronic acid in the presence of a catalyst such as tetrakis(triphenylphosphine) palladium(0), and a base such as sodium carbonate, in anl inert solvent such as DME at about 80xc2x0 C. The free hydroxamic acids may be liberated as previously described.
Scheme 10 shows a method of preparing hydroxamic acids having amine groups attached to the aromatic ring. 
Reagents and Conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotiiazole hydrate (HOBt, 6.0 eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25xc2x0 C.; 2-16 hours. b) 4-Bromobenzenethiol (5.0 eq.); sodium iodide (5.0 eq.); 1,8-diazabicyclo[5.4.0]undec-7ene (DBU, 3.0 eq.); TBF; 25xc2x0 C.; 12-16 hours. c) Amine (20.0 eq.); tris(dibenzylideneacetone)-dipalladium(0) (0.2 eq.); (S)-(xe2x88x92)-2,2xe2x80x2-bis(diphenylphosphimo)-1,1xe2x80x2-binaphthyl ((S)-BINAP, 0.8 eq.); sodium tert-butoxide (18.0 eq.); dioxane; 80xc2x0 C., 8 hours; d) TFA: DCM (1:1); 25xc2x0 C.; 1 hour.
The hydroxylamine resin may be coupled with the 2-halo acid and the halo group may be displaced by bromobenzenethiol as previously described. The bromo group may then be displaced with an amine in the presence of a catalyst such as tds(dibenzylideneacetone)-dipalladium(0) and a ligand such as (S)-BINAP and a base such as sodium tert-butoxide, in an inert solvent such as dioxane at about 80xc2x0 C. The free hydroxarnic acids may be hberated as previously described.
Scheme 11 shows a method of preparing hydroxamic acids having sulfonate groups attached to the aromatic ring. 
Reagents and Conditions: a) 2-Halo acid (3.0 eq.); 1-hydroxybenzotriazole hydrate (HOBt, 6.0 eq.); 1,3-diisopropylcarbodiimide (DIC, 4.0 eq.); DMF, 25xc2x0 C.; 2-16 hours. b) 4-Hydroxybenzenethiol (5.0 eq.); sodium iodide (5.0 eq.); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0 eq.); THF; 25xc2x0 C.; 12-16 hours. c) Sulfonyl chloride (5.0 eq.); triethylamine (2.0 eq.); DCM; 25xc2x0 C.; 8 hours. d) 70% tert-butylhydroperoxide (40 eq.); benzenesulfonic acid (2.0 eq.); DCM; 25xc2x0 C.; 12-24 hours. e) mCPBA (5.0 eq.); DCM; 25xc2x0 C.; 12-24 hours. f) TFA: DCM (1:1); 25xc2x0 C.; 1 hour.
The hydroxylanmine resin may be coupled with the 2-halo acid and the halo group may be displaced by hydroxybenzenethiol as previously described. The hydroxybenzenesulfanyl hydroxamate ester may then be oxidized either to the corresponding sulfinyl or sulfonyl hydroxamate ester as previously described. The hydroxy group may then be sulfonylated by reaction with a sulfonyl chloride in the presence of a base such as triethylamine, in an inert solvent such as DCM at about room temperature. The free hydroxamic acids may be liberated as previously described.
The following examples are presented to illustrate rather than limit the scope of the invention. HPLC purity of compounds prepared by combinatorial procedures is presented as area percentage at a prescribed wavelength (% @ nm).